This invention relates to imidazoquinoline compounds that have sulfonamide or sulfamide substitution at the 1-position and to pharmaceutical compositions containing the compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases.
The invention is directed to methods for the treatment or prevention of periodontal conditions. Specifically the invention includes the novel use of immune response modifier compounds to treat or prevent periodontal disease. Preferred immune response modifiers are selected from the group of immune response modifiers comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.
The first reliable report on the 1H-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H-imidazo[4,5-c]quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-c]quinolines.
Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system, as seen for example in WO 98/30562, EP 894 797 and WO 00/09506. EP 894 797 discloses amide substituted imidazoquinoline compounds that are disclosed to be useful as immune response modifying compounds, while WO 00/09506 discloses imidazoquinoline compounds that contain a sulfonamide substituent wherein the sulfonamide nitrogen is part of a saturated heterocyclic ring. Despite these efforts, however, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
Periodontal disease or periodontitis is an inflammatory disease that results in the destruction of both the hard and soft tissues supporting the teeth and has recently been hypothesized as a risk factor for cardiovascular disease. Beck et al. xe2x80x9cDental Infections and atherosclerosis, xe2x80x9dAmerican Heart Journal, 13:S528-533 (1999). It is estimated that over 10 million people in the United States are currently being treated for the more serious forms of this disease, with approximately 8 billion dollars spent for treatment each year.
Clinically, periodontitis is an inflammation of the periodontium that results in inflammation of the gingiva and may result in resorption of alveolar bone and recession of the gingiva. Recession of the gingiva can lead to exposure of the periodontal ligament allowing microorganisms to invade and destroy the ligament.
Infection by a few essential species of bacteria is important in initiating the host inflammatory response that is responsible for the tissue destruction and ultimate loss of teeth. Zambon, J. J., xe2x80x9cPeriodontal Disease, Microbial Factors,xe2x80x9dAnn. Periodontol., 1:879-825 (1996). The major pathogens associated with the disease have been identified and include Porphyromonas gingivalis, Bacteroides forsythus and Actinobacillus actinomycetemcomitans. Although essential to the pathogenesis, bacteria alone are insufficient to cause the disease. Host factors such as hereditary predisposition and environmental factors such as smoking are believed to equally effect disease occurrence and severity of outcome.
Forms of periodontitis include early onset periodontitis (EOP), chronic adult periodontitis (AP), and refractory periodontitis (RP). Localized juvenile periodontitis is a form of EOP which occurs in otherwise seemingly healthy adolescents and is associated with infection by A. actinomycetemcomitans. xe2x80x9cChronic adult periodontitisxe2x80x9d is commonly associated with the presence of B. forsythus, P. gingivalis,many gram-negative asaccharolytic rods, and oral spirochetes. It typically occurs in patients over 35 years of age. Clinically, it resembles acute necrotizing ulcerative gingivitis imposed on rapidly progressive periodontitis. Patients may lose 9 to 12 mm of gingival attachment in as little as six months.
Current treatment for periodontal disease is almost exclusively mechanical and surgical in nature most frequently including scaling and root planing to remove calculus deposits. However, the mechanical treatments do not affect the underlying cause of disease. Antibiotics have also been used as an adjunct therapy, Loesche et al, xe2x80x9cTreatment paradigms in periodontal diseasexe2x80x9d, Compend. Contin. Educ Dental, 18(3):221-6, 228-30 (1997). Unfortunately, results have been disappointing because the antibiotic may not eliminate the bacteria responsible for the inflammatory component, and patients are subject to re-infection.
Accordingly, there is a continuing need for new and effective treatment and preventive measures for periodontal disease. The present invention is directed to this need.
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides compounds of Formula I: 
wherein R, R1 and R2 are as defined herein.
The compounds of Formula I are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I and methods of inducing cytokine biosynthesis in an animal, treating a viral infection and/or treating a neoplastic disease in an animal by administering a effective amount of a compound of Formula I to the animal.
In addition, methods of synthesizing compounds of Formula I and intermediates useful in the synthesis of these compounds are provided.
The present invention provides methods for treating or preventing a periodontal condition comprising administering a therapeutically effective amount of an immune response modifier (IRM) compound directly to periodontal tissue in a patient affected by the periodontal condition. In preferred embodiments the IRM compound is selected from the group comprising imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines and 1,2-bridged imidazoquinoline amines.